Alfred Blalock was born in Culloden, Georgia in 1899 to a prominent business family. After graduating from the University of Georgia, he studied medicine at Johns Hopkins University, where he finished his residency. From 1925 to 1941, Blalock worked as resident surgeon at Vanderbilt University's medical school, his second choice after Hopkins. There, he and Vivien Thomas conducted research that ultimately showed that surgical shock was caused by loss of blood volume. While working at Vanderbilt, Blalock contracted tuberculosis; he recovered after treatment and was even more committed to research.

As a result of his Vanderbilt research on the physiology of shock, Blalock urged wider use of plasma or whole-blood transfusions to improve treatment for surgical shock. That finding saved millions of lives in World War II alone.

In 1941, Blalock joined the surgery staff of Johns Hopkins University, in Baltimore. He brought Thomas with him to collaborate on technical developments and supervise the experimental lab. At Hopkins, Blalock met Dr. Helen Taussig, head of the children's heart clinic at Hopkins. Taussig was concerned for children who suffered from the heart defect Tetralogy of Fallot, and speculated that the defect was caused by an obstruction of passages from the heart to the pulmonary arteries. Blalock accepted her challenge to develop a surgical procedure to relieve that obstruction. First, with Thomas, he demonstrated that Taussig's hypothesis was correct in laboratory animals. Then he and Thomas worked with Taussig to develop the procedure, known as the Blalock-Taussig shunt, that would alleviate the obstruction.

In 1944 Blalock, with Thomas advising over his shoulder, performed the first "blue baby" operation on 15-month-old Eileen Saxon. The operation was a success, although Saxon later died. In the following months and years, Blalock performed the procedure on thousands of children, often accompanied by Vivien Thomas. The operation not only directly saved thousands of lives, it marked the start of the modern era of cardiac surgery.

Blalock continued research on vascular surgery. With Edwards Park, he developed a bypass operation for coarctation of the aorta in 1944; and with Rollins Hanlon, he created a technique for overcoming another congenital defect, the transposition of the great blood vessels of the heart, in 1948. In teaching and in research he paved the way for a new generation of surgeons.

Blalock received numerous awards and honorary degrees. He died in 1964, leaving his wife, three children, and a legacy of healing and medical breakthroughs.